Two observations suggest that the Interferon Consensus Sequence Binding Protein (ICSBP) is necessary for normal myeloid differentiation. The first observation is that ICSBP -/- mice have myeloid expansion and impaired immune function. This suggests that ICSBP is necessary for progression of differentiation. The second observation is that ICSBP expression is decreased in human myeloid malignancy, and 1CSBP -/- mice develop myeloid leukemia. This suggests that ICSBP is a "leukemia suppressor", during myeloid differentiation. We found that tyrosine phosphorylated ICSBP interacts with PU.1, Interferon Regulatory Factor 1, and the CREB-binding protein, during late myeloid differentiation. This interaction activates genes encoding the respiratory burst oxidase proteins, gp91phox and p67phoX. These results suggest that ICSBP activates transcription of genes that confer the mature phagocyte phenotype. In contrast, non-tyrosine phosphorylated ICSBP represses Bcl-XL expression in undifferentiated myeloid cells. This suggests that ICSBP influences initiation of apoptosis during early differentiation. Therefore, ICSBP tyrosine phosphorylation, which occurs during myelopoiesis, alters protein-DNA and protein-protein interactions. Based on these observations, we hypothesize that ICSBP participates in phosphorylation dependent protein-protein interactions, which regulate differentiation-stage-specific myeloid gene expression and are necessary for differentiation progression. We also hypothesize that ICSBP tyrosine phosphorylation induces functional switch from repressor to activator. The following aims will pursue these hypotheses; Aim 1: Determine if ICSBP tyrosine phosphorylation is necessary for progression of myeloid differentiation. Aim 2: Determine if ICSBP function switches from repression to activation during myeloid differentiation. Aim 3: Determine if ICSBP tyrosine phosphorylation is necessary for "tumor suppression" in ICSBP -/- mice. These studies will determine if ICSBP tyrosine phosphorylation is necessary for myeloid differentiation and leukemia suppression, providing a unique model to dissect early events in the evolution of myeloid malignancy.